Abstract Background Telemedicine is changing traditional nursing care, and entails nurses performing advanced and complex care within a new clinical environment, and monitoring patients at a distance. Telemedicine practice requires complex disease management, advocating that the nurses’ reasoning and decision-making processes are supported. Computerised decision support systems are being used increasingly to assist reasoning and decision-making in different situations. However, little research has focused on the clinical reasoning of nurses using a computerised decision support system in a telemedicine setting. Therefore, the objective of the study is to explore the process of telemedicine nurses’ clinical reasoning when using a computerised decision support system for the management of patients with chronic obstructive pulmonary disease. The factors influencing the reasoning and decision-making processes were investigated. Methods In this ethnographic study, a combination of data collection methods, including participatory observations, the think-aloud technique, and a focus group interview was employed. Collected data were analysed using qualitative content analysis. Results When telemedicine nurses used a computerised decision support system for the management of patients with complex, unstable chronic obstructive pulmonary disease, two categories emerged: “the process of telemedicine nurses’ reasoning to assess health change” and “the influence of the telemedicine setting on nurses’ reasoning and decision-making processes”. An overall theme, termed “advancing beyond the system”, represented the connection between the reasoning processes and the telemedicine work and setting, where being familiar with the patient functioned as a foundation for the nurses’ clinical reasoning process. Conclusion In the telemedicine setting, when supported by a computerised decision support system, nurses’ reasoning was enabled by the continuous flow of digital clinical data, regular video-mediated contact and shared decision-making with the patient. These factors fostered an in-depth knowledge of the patients and acted as a foundation for the nurses’ reasoning process. Nurses’ reasoning frequently advanced beyond the computerised decision support system recommendations. Future studies are warranted to develop more accurate algorithms, increase system maturity, and improve the integration of the digital clinical information with clinical experiences, to support telemedicine nurses’ reasoning process.